JP2008214351A - Ep2 acceptor agonist as ocular pressure reducer - Google Patents
Ep2 acceptor agonist as ocular pressure reducer Download PDFInfo
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Classifications
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- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C69/00—Esters of carboxylic acids; Esters of carbonic or haloformic acids
- C07C69/66—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety
- C07C69/73—Esters of carboxylic acids having esterified carboxylic groups bound to acyclic carbon atoms and having any of the groups OH, O—metal, —CHO, keto, ether, acyloxy, groups, groups, or in the acid moiety of unsaturated acids
- C07C69/738—Esters of keto-carboxylic acids or aldehydo-carboxylic acids
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K31/00—Medicinal preparations containing organic active ingredients
- A61K31/557—Eicosanoids, e.g. leukotrienes or prostaglandins
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P27/00—Drugs for disorders of the senses
- A61P27/02—Ophthalmic agents
- A61P27/06—Antiglaucoma agents or miotics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C405/00—Compounds containing a five-membered ring having two side-chains in ortho position to each other, and having oxygen atoms directly attached to the ring in ortho position to one of the side-chains, one side-chain containing, not directly attached to the ring, a carbon atom having three bonds to hetero atoms with at the most one bond to halogen, and the other side-chain having oxygen atoms attached in gamma-position to the ring, e.g. prostaglandins ; Analogues or derivatives thereof
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
- C07C2601/00—Systems containing only non-condensed rings
- C07C2601/06—Systems containing only non-condensed rings with a five-membered ring
- C07C2601/08—Systems containing only non-condensed rings with a five-membered ring the ring being saturated
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- Chemical & Material Sciences (AREA)
- Organic Chemistry (AREA)
- Health & Medical Sciences (AREA)
- General Health & Medical Sciences (AREA)
- Public Health (AREA)
- Veterinary Medicine (AREA)
- Medicinal Chemistry (AREA)
- Animal Behavior & Ethology (AREA)
- Life Sciences & Earth Sciences (AREA)
- Pharmacology & Pharmacy (AREA)
- Bioinformatics & Cheminformatics (AREA)
- Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
- Engineering & Computer Science (AREA)
- Chemical Kinetics & Catalysis (AREA)
- General Chemical & Material Sciences (AREA)
- Ophthalmology & Optometry (AREA)
- Epidemiology (AREA)
- Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
- Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
Abstract
Description
発明の分野
本発明は、哺乳動物の眼圧を降下するため、およびそれ故、緑内障の処置に有用な、ＥＰ2受容体作動剤の用途に関する。とりわけ、(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸、並びにそのエステルおよび不飽和誘導体が、緑内障の処置に有効である。
FIELD OF THE INVENTION This invention relates to the use of EP 2 receptor agonists for lowering intraocular pressure in mammals and therefore useful for the treatment of glaucoma. In particular, (±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid and its esters and unsaturated derivatives are effective in the treatment of glaucoma.
発明の背景
眼圧降下剤は、多様な高眼圧症状、例えば術後およびレーザートラベクレクトミー後の高眼圧や、緑内障の処置において、並びに術前の補助薬として有用である。
緑内障は、眼圧の上昇により特徴付けられる眼疾患である。緑内障は、その病因により、原発性または続発性として分類されている。例えば、成人の原発性緑内障(先天性緑内障)は、開放隅角緑内障であるか、または急性もしくは慢性の閉塞隅角緑内障であり得る。続発性緑内障は、ブドウ膜炎、眼内腫瘍または拡大した白内障のような既存の眼疾患から生じる。
BACKGROUND OF THE INVENTION Intraocular pressure-lowering agents are useful in the treatment of various high intraocular pressure symptoms, such as high intraocular pressure after surgery and after laser trabeculectomy, glaucoma and as a preoperative adjuvant.
Glaucoma is an eye disease characterized by increased intraocular pressure. Glaucoma is classified as primary or secondary depending on its etiology. For example, an adult primary glaucoma (congenital glaucoma) can be open-angle glaucoma or acute or chronic angle-closure glaucoma. Secondary glaucoma arises from existing eye diseases such as uveitis, intraocular tumors or enlarged cataracts.
原発性緑内障の原因は、未だ解明されていない。その眼圧上昇は、房水流出遮断による。慢性開放隅角緑内障においては、前房およびその解剖学的構造は正常に見えるが、房水の排出は妨げられる。急性または慢性の閉塞隅角緑内障においては、前房が浅く、透過角が狭く、虹彩がシュレンム管の入口の小柱網を閉塞し得る。瞳孔の拡張により、虹彩根部が隅角に対して前方に押され、および瞳孔ブロックを起こして、病状を急進し得る。前房隅角の狭い眼は、種々の重篤度の急性閉塞隅角緑内障に患る素因を有する。 The cause of primary glaucoma has not yet been elucidated. The increase in intraocular pressure is due to blockage of aqueous humor outflow. In chronic open-angle glaucoma, the anterior chamber and its anatomy appear normal, but drainage of the aqueous humor is impeded. In acute or chronic angle-closure glaucoma, the anterior chamber is shallow, the transmission angle is narrow, and the iris can block the trabecular meshwork at the entrance of Schlemm's canal. The dilation of the pupil can push the iris root forward with respect to the corner and cause a pupil block to accelerate the pathology. Eyes with a narrow anterior chamber angle are predisposed to suffering from acute closed angle glaucoma of varying severity.
続発性緑内障は、後房から前房、次いでシュレンム管への房水の流れのいかなる妨害によっても起こる。前房の炎症性疾患は、膨隆虹彩における完全な虹彩後癒着を起こすことにより房水排出を妨げ得、排液路を滲出物で閉塞し得る。他の通常の原因は、眼内腫瘍、拡大した白内障、網膜中心静脈閉塞、眼の外傷、手術操作および眼内出血である。
すべての種類を考慮すると、緑内障は、４０歳を超えるすべての人の約２％に起こり、視力が急速に損われるまで何年間も無症候性であり得る。手術が指示されない場合、局所用β−アドレナリン受容体拮抗剤が、従来、緑内障処置薬物として選択されている。
Secondary glaucoma is caused by any obstruction of the flow of aqueous humor from the posterior chamber to the anterior chamber and then to Schlemm's canal. Inflammatory diseases of the anterior chamber can impede aqueous humor drainage by causing complete post-iris adhesions in the bulging iris and block the drainage tract with exudates. Other common causes are intraocular tumors, enlarged cataracts, central retinal vein occlusion, eye trauma, surgical procedures and intraocular bleeding.
Considering all types, glaucoma occurs in about 2% of all people over the age of 40 and can be asymptomatic for years until vision is rapidly impaired. Where surgery is not indicated, topical β-adrenergic receptor antagonists are traditionally selected as glaucoma treatment drugs.
プロスタグランジンはかつて、有効な眼圧上昇剤であると見なされていた；しかし、過去２０年間に蓄積された証拠によると、いくつかのプロスタグランジンは非常に有効な眼圧降下剤であり、緑内障の長期処置に好適であることがわかった。[例えば、スター，エム・エス(Ｓtarr，Ｍ．Ｓ．)、エクスペリメンタル・アイ・リサーチ(Ｅxp．Ｅye Ｒes．)、１９７１、１１、第１７０〜１７７頁；ビト，エル・ゼット(Ｂito，Ｌ．Ｚ．)、バイオロジカル・プロテクション・ウィズ・プロスタグランジンズ(Ｂiological Ｐrotection with Ｐrostagandins)、コーヘン，エム・エム(Ｃohen，Ｍ．Ｍ．)編、ボカ・レイトン(Ｂoca Ｒaton)、フロリダ、ＣＲＣプレス社(ＣＲＣ Ｐress Ｉnc．)、１９８５、第２３１〜２５２頁；並びにビト，エル・ゼット、アプライド・ファーマコロジー・イン・ザ・メディカル・トリートメント・オブ・グラウコマズ(Ａpplied Ｐharmacology in the Ｍedical Ｔreatment of Ｇlaucomas)、ドランス，エス・エム(Ｄrance，Ｓ．Ｍ．)およびニューフェルド，エイ・エイチ(Ｎeufeld，Ａ．Ｈ．)編、ニューヨーク、グルーン・アンド・ストラットン(Ｇrune ＆ Ｓtratton)、１９８４、第４７７〜５０５頁参照。]そのようなプロスタグランジンは、ＰＧＦ2α、ＰＧＦ1α、ＰＧＥ2、およびそれらの脂溶性エステル(例えば、１−イソプロピルエステルのようなＣ1−Ｃ5アルキルエステル)を包含する。 Prostaglandins were once considered to be effective intraocular pressure raising agents; however, according to the evidence accumulated over the past 20 years, some prostaglandins are very effective intraocular pressure-lowering agents. It was found to be suitable for long-term treatment of glaucoma. [E.g., Starr, MS, Exp. Eye Res., 1971, 11, pp. 170-177; Vito, El. L.Z.), Biological Protection with Prostaglandins, edited by Cohen, M.M., Boca Raton, Florida, CRC Press (CRC Press Inc.), 1985, pp. 231-252; and Vito, El Zett, Applied Pharmaceuticals in the Medical Treatment of Glaucomas, Edited by Drance, SM, and Newfeld, AH, New York , Greencastle-and-Stratton (Grune & Stratton), 1984, pp. 477-505. Such prostaglandins include PGF 2α , PGF 1α , PGE 2 , and their fat-soluble esters (eg, C 1 -C 5 alkyl esters such as 1-isopropyl ester).
米国特許第４５９９３５３号において、ある種のプロスタグランジン、とりわけＰＧＥ2およびＰＧＦ2α並びに後者のＣ1−Ｃ5アルキルエステルが眼圧降下活性を有することが報告され、緑内障処置に使用することが提案された。
プロスタグランジンによる眼圧降下の詳しいメカニズムは未だわかっていないが、最近の実験結果により、ブドウ膜強膜流出の増加によるものであることが示された[ニルソン(Ｎilsson)ら、インベスティゲイティブ・オフサルモロジー・アンド・ビジュアル・サイエンス(Ｉnvest．Ｏphthalmol．Ｖis．Ｓci．)２８(補遺)、２８４(１９８７)]。
In US Pat. No. 4,599,353, certain prostaglandins, especially PGE 2 and PGF 2α and the latter C 1 -C 5 alkyl esters are reported to have intraocular pressure-lowering activity and are proposed for use in the treatment of glaucoma. It was done.
The detailed mechanism of intraocular pressure drop by prostaglandins is not yet known, but recent experimental results have shown that it is due to increased uveoscleral outflow [Nilsson et al., Investigative Ovsalmology and Visual Science (Invest. Ophthalmol. Vis. Sci.) 28 (Supplement), 284 (1987)].
ＰＧＦ2αのイソプロピルエステルは、親化合物よりもはるかに大きい降圧活性を有することがわかっている。これは、角膜透過性がより高いことによると考えられる。１９８７年にこの化合物は、「かつて報告されたうちで最も強力な眼圧降下剤」であると文献に記載された[例えば、ビト，エル・ゼット、アーカイブズ・オブ・オフサルモロジー(Ａrch．Ｏphthalmol．)、１０５、１０３６(１９８７)、およびシーボルド(Ｓiebold)ら、プロドラッグ(Ｐrodrug)５、３(１９８９)参照]。
プロスタグランジンは顕著な眼内副作用を持たないと考えられるが、眼表面(結膜)充血および異物感は、ヒトの眼に対するそのような化合物(とりわけＰＧＦ2αおよびそのプロドラッグ、例えば１−イソプロピルエステル)の局所適用に伴って起こる。高眼圧を伴う症状(例えば緑内障)の処置におけるプロスタグランジンの臨床的使用可能性は、上記のような副作用の故に非常に制限されている。
The isopropyl ester of PGF 2α has been found to have much greater antihypertensive activity than the parent compound. This is thought to be due to higher corneal permeability. In 1987, this compound was described in the literature as “the most potent ocular hypotensive agent ever reported” [eg, Vito, El Zett, Archives of Ophthalmolology (Arch. Ophthalmol). ), 105, 1036 (1987), and Siebold et al., Prodrug 5, 3 (1989)].
Although prostaglandins are not believed to have significant intraocular side effects, ocular surface (conjunctival) hyperemia and foreign body sensation are such compounds (especially PGF 2α and its prodrugs such as 1-isopropyl ester) for the human eye. ) Occurs with topical application. The clinical potential of prostaglandins in the treatment of symptoms with high intraocular pressure (eg glaucoma) is very limited due to side effects as described above.
欧州特許出願第０３６４４１７号においては、ある種のフェニルおよびフェノキシモノ、トリおよびテトラノルプロスタグランジン、並びにその１−エステルが、緑内障または高眼圧の処置に有用であると開示されている。
アラーガン社(Ａllergan，Ｉnc．)に譲渡された一連の同時係属米国特許出願において、眼圧降下活性が高く、副作用は無い、または実質的に副作用の無いプロスタグランジンエステルが開示されている。同時係属米国特許出願第３８６８３５号(１９８９年７月２７日出願)は、ある種の１１−アシル−プロスタグランジン、例えば１１−ピバロイル、１１−アセチル、１１−イソブチリル、１１−バレリル、および１１−イソバレリルＰＧＦ2αに関する。同時係属米国特許出願第３５７３９４号(１９８９年５月２５日出願)には、眼圧降下作用を有する１５−アシルプロスタグランジンが開示されている。同様に、プロスタグランジンの１１,１５−、９,１５−および９,１１−ジエステル、例えば１１,１５−ジピバロイルＰＧＦ2αも、眼圧降下活性を有することが知られている。同時係属米国特許出願第３８５６４５号（１９９０年７月２７日出願、米国特許第４４９４２７４号に対応）；第５８４３７０号(米国特許出願第３８６３１２号の継続出願)；第５８５２８４号（米国特許第５０３４４１３号に対応、米国特許出願第３８６８３４号の継続出願）(親出願は１９８９年７月２７日出願)参照。上記特許出願の開示を、特に引用により本発明の一部とする。
In European Patent Application No. 0364417, certain phenyl and phenoxymono, tri and tetranor prostaglandins and their 1-esters are disclosed as being useful for the treatment of glaucoma or high intraocular pressure.
In a series of co-pending US patent applications assigned to Allergan, Inc., prostaglandin esters with high intraocular pressure-lowering activity, no side effects, or substantially no side effects are disclosed. Co-pending U.S. Patent Application No. 386835 (filed July 27, 1989) includes certain 11-acyl-prostaglandins such as 11-pivaloyl, 11-acetyl, 11-isobutyryl, 11-valeryl, and 11- It relates to isovaleryl PGF 2α . Co-pending US Patent Application No. 357394 (filed May 25, 1989) discloses 15-acyl prostaglandins having an intraocular pressure-lowering effect. Similarly, 11,15-, 9,15- and 9,11-diesters of prostaglandins, such as 11,15-dipivaloyl PGF 2α , are known to have intraocular pressure-lowering activity. Co-pending U.S. Patent Application No. 385645 (filed July 27, 1990, corresponding to U.S. Pat. No. 4,494,274); No. 584370 (Continuation of U.S. Patent Application No. 386,612); No. 585284 (U.S. Pat. No. 5,034,413) (Continuation of US Patent Application No. 386834) (the parent application was filed on July 27, 1989). The disclosure of the above patent application is specifically incorporated herein by reference.
また、ニアルス(Ｎials)ら、カルディオヴァスキュラー・ドラッグ・レビューズ(Ｃardiovascular Ｄrug Ｒeviews)、第１１巻、第２号、第１６５−１７９頁；コールマン(Ｃoleman)ら、コンプリヘンシブ・メディシナール・ケミストリー(Ｃomprehenisive Ｍedicinal Ｃhemistry)、第３巻、第６４３−７１４頁、１９９０；およびウッドウォード(Ｗoodward)ら、プロスタグランジンズ(Ｐrostaglandins)、第３７１−３８３頁、１９９３には、ある種のＥＰ2受容体作動剤が開示されている。 Also, Nials et al., Cardiovascular Drug Reviews, Vol. 11, No. 2, pp. 165-179; Coleman et al., Comprehensive Medicinal Chemistry. (Comprehenisive Medicinal Chemistry), Volume 3, pages 643-714, 1990; and Woodward et al., Prostaglandins, pages 371-383, 1993, contain certain EP 2 receptors. An agonist is disclosed.
発明の概要
ある種のＥＰ2受容体作動剤は、有効な眼圧降下剤であることがわかった。更に、(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸並びにそのエステルおよび不飽和誘導体は、緑内障の処置に特に有用であり、驚くべきことに、眼表面の充血を起こさないか、または眼圧降下に有用な他の化合物(例えばＰＧＦ2αおよびその低級アルキルエステル)よりも顕著に軽度にしか起こさないということがわかった。
SUMMARY OF THE INVENTION Certain EP 2 receptor agonists have been found to be effective intraocular pressure-lowering agents. Furthermore, (±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid and its esters and unsaturated derivatives are particularly useful for the treatment of glaucoma and surprisingly It has been found that it does not cause ocular hyperemia or is significantly less severe than other compounds useful for lowering intraocular pressure (eg, PGF 2α and its lower alkyl esters).
本発明は、高眼圧を処置する方法であって、式Ｉ：
より好ましくは、本発明の方法は、式II：
で示される化合物を投与することを含んで成る。
本発明は、式(Ｉ)または(II)[記号は前記と同意義]で示される化合物または薬学的に許容し得るその塩の処置有効量を、薬学的に許容し得る無毒性液体賦形剤と共に含有する薬剤組成物にも関する。
More preferably, the method of the present invention has formula II:
Administering a compound of formula I.
The present invention provides a therapeutically effective amount of a compound represented by formula (I) or (II) [wherein the symbols are as defined above] or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable non-toxic liquid excipient. It also relates to a pharmaceutical composition contained with the agent.
本発明は、前記式[置換基および記号は前記と同意義]で示される、ある種の(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸並びにそのエステルおよび不飽和誘導体、または薬学的に許容し得るその塩にも関する。 The present invention relates to a certain (±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid represented by the above formula [substituents and symbols are as defined above]. As well as its esters and unsaturated derivatives, or pharmaceutically acceptable salts thereof.
発明の詳細な説明
本発明は、(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸並びにそのエステルおよび不飽和誘導体の、眼圧降下剤としての用途に関する。本発明の処置剤は、前記のような式Ｉ：
[式中、Ｒ2は低級アルキル基である。]で示される。
DETAILED DESCRIPTION OF THE INVENTION The present invention relates to (±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid and its esters and unsaturated derivatives as ocular hypotensive agents. Regarding usage. The treatment of the present invention is a compound of formula I as described above:
[Wherein R 2 represents a lower alkyl group. ] Is shown.
Ｈ2)基、すなわち、ヘキシレニル基である。５位および６位の炭素間(Ｃ−５)の結合における点線は、その部分の結合が一重結合であるか、またはシスもしくはトランス配置であり得る二重結合であることを表す。その二重結合に隣接する基は、ＣＨ基である。２本の実線を用いる場合は、二重結合の配置を特定して示す。Ｃ−９およびＣ−１１の位置におけるハッチングした線はα配置を表す。β配置は、三角形に塗り潰した線で示す。
本発明に従って使用する化合物は、αまたはβ配置のＣ−９またはＣ−１１置換基を有する化合物を包含する。前記のように、本明細書中のいずれの式においても、ハッチングした線で示すシクロペンタン環への結合は、置換基がα配置であることを意味する。太い実線で示すシクロペンタン環への結合は、置換基がβ配置であること意味する。
H 2 ) group, ie a hexylenyl group. The dotted line in the bond between carbons 5 and 6 (C-5) indicates that the bond at that part is a single bond or a double bond that can be in the cis or trans configuration. The group adjacent to the double bond is a CH group. When two solid lines are used, the arrangement of double bonds is specified and shown. The hatched lines at C-9 and C-11 represent the α configuration. The β arrangement is indicated by a solid line.
Compounds used in accordance with the present invention include compounds having a C-9 or C-11 substituent in the α or β configuration. As described above, in any formula in this specification, the bond to the cyclopentane ring indicated by the hatched line means that the substituent is in the α configuration. The bond to the cyclopentane ring indicated by the bold solid line means that the substituent is in the β configuration.
本発明において、特記しない限り、「アルキル」とは、炭素数１〜１０のアルキル基を意味し、炭素数１〜５の「低級アルキル」基を包含し、「シクロアルキル」とは、炭素数３〜７のシクロアルキル基を意味し、「アリール」とは、炭素数４〜１０のアリール基を意味する。「飽和または不飽和非環式炭化水素基」は、炭素数１〜約６(好ましくは１〜約４)の直鎖または分枝鎖の飽和または不飽和炭化水素基を意味する。そのような基は、適当な鎖長のアルキル、アルケニルおよびアルキニル基を包含し、好ましくはアルキル、例えばメチル、エチル、プロピル、ブチル、ペンチルもしくはヘキシルまたはそれらの異性体である。 In the present invention, unless otherwise specified, “alkyl” means an alkyl group having 1 to 10 carbon atoms, includes “lower alkyl” groups having 1 to 5 carbon atoms, and “cycloalkyl” means carbon atoms. A cycloalkyl group having 3 to 7 is meant, and “aryl” means an aryl group having 4 to 10 carbon atoms. “Saturated or unsaturated acyclic hydrocarbon group” means a straight or branched chain saturated or unsaturated hydrocarbon group having 1 to about 6 carbon atoms (preferably 1 to about 4 carbon atoms). Such groups include alkyl, alkenyl and alkynyl groups of appropriate chain length, preferably alkyl such as methyl, ethyl, propyl, butyl, pentyl or hexyl or isomers thereof.
Ｒの定義は、環成分−(ＣＨ2)mＲ1[mは０〜１０であり、Ｒ2は炭素数約３〜７の脂環であるか、または芳香環もしくは複素環である。]を包含し得る。「脂環」は、飽和または不飽和であり得、好ましくは炭素数３〜７の飽和環である。芳香環としてはＲ1は好ましくはフェニルであり、複素環はヘテロ原子として酸素、窒素またはイオウを有し、Ｒ1はチエニル、フラニル、ピリジルなどであり得る。mは好ましくは０〜４である。
本発明の化合物の好ましい例は、(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸、その不飽和誘導体、およびそれらの低級アルキルエステルである。
(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸を、本発明の薬剤組成物および処置方法において使用し得る。
R is defined as a ring component — (CH 2 ) mR 1, where m is 0 to 10 and R 2 is an alicyclic ring having about 3 to 7 carbon atoms, or an aromatic ring or a heterocyclic ring. ] May be included. The “alicyclic ring” may be saturated or unsaturated, and is preferably a saturated ring having 3 to 7 carbon atoms. As an aromatic ring, R 1 is preferably phenyl, the heterocycle has oxygen, nitrogen or sulfur as a heteroatom, and R 1 can be thienyl, furanyl, pyridyl, and the like. m is preferably 0-4.
Preferred examples of the compounds of the present invention are (±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid, its unsaturated derivatives, and their lower alkyl esters.
(±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid may be used in the pharmaceutical compositions and treatment methods of the invention.
本発明の化合物の薬学的に許容し得る塩は、親化合物の活性を保持し、被投与体および投与を行う環境に対して不都合な影響を及ぼさないいずれの塩であってもよい。そのような塩は、例えばアルカリ金属、アルカリ土類金属などの薬学的に許容し得る陽イオンと共に形成した塩である。
薬剤組成物は、少なくとも１種の本発明化合物または薬学的に許容し得るその塩の処置有効量を活性成分として、眼科学的に許容し得る通常の薬剤賦形剤と組み合わせることによって、および点眼に適当な単位用量形態を形成することによって調製し得る。処置有効量は通例、液体製剤中約０.０００１〜５％(w／v)、好ましくは約０.００１〜１.０％(w／v)である。
The pharmaceutically acceptable salt of the compound of the present invention may be any salt that retains the activity of the parent compound and does not adversely affect the subject and the environment in which it is administered. Such salts are salts formed with pharmaceutically acceptable cations such as alkali metals, alkaline earth metals and the like.
The pharmaceutical composition comprises a therapeutically effective amount of at least one compound of the present invention or a pharmaceutically acceptable salt thereof as an active ingredient in combination with conventional ophthalmologically acceptable pharmaceutical excipients and eye drops Can be prepared by forming a suitable unit dosage form. A therapeutically effective amount is typically about 0.0001 to 5% (w / v), preferably about 0.001 to 1.0% (w / v) in a liquid formulation.
眼科的な適用のためには、主な賦形剤として生理食塩液を用いて溶液を調製することが好ましい。そのような眼用溶液のpＨは、適当な緩衝系によって４.５〜８.０に保つことが好ましい。中性pＨが好ましいが、本質的ではない。このような製剤は、薬学的に許容し得る通常の保存剤、安定剤および界面活性剤をも含有し得る。
本発明の薬剤組成物中に使用し得る好ましい保存剤は、塩化ベンザルコニウム、クロロブタノール、チメロサール、酢酸フェニル水銀および硝酸フェニル水銀を包含するが、これらに限定されるものではない。好ましい界面活性剤は、例えば、トゥイーン(Ｔween)８０である。同様に、本発明の眼用製剤中に種々の好ましい賦形剤を使用し得る。このような賦形剤は、ポリビニルアルコール、ポリビニルピロリドン、ヒドロキシプロピルメチルセルロース、ポロキサマー、カルボキシメチルセルロース、ヒドロキシエチルセルロース、シクロデキストリンおよび精製水を包含するが、これらに限定されるものではない。
For ophthalmic applications, it is preferable to prepare solutions using physiological saline as the main excipient. The pH of such an ophthalmic solution is preferably maintained at 4.5 to 8.0 with an appropriate buffer system. Neutral pH is preferred but not essential. Such formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers and surfactants.
Preferred preservatives that can be used in the pharmaceutical compositions of the present invention include, but are not limited to, benzalkonium chloride, chlorobutanol, thimerosal, phenylmercuric acetate and phenylmercuric nitrate. A preferred surfactant is, for example, Tween 80. Similarly, various preferred excipients may be used in the ophthalmic formulations of the present invention. Such excipients include, but are not limited to, polyvinyl alcohol, polyvinyl pyrrolidone, hydroxypropyl methylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, cyclodextrin and purified water.
必要に応じて、または好都合に、浸透圧調整剤を添加し得る。浸透圧調整剤は、塩、とりわけ塩化ナトリウム、塩化カリウム、マンニトールおよびグリセリンを包含するが、これらに限定されるものではなく、眼科学的に許容し得る他の適当な浸透圧調整剤も使用し得る。
眼科学的に許容し得る製剤が得られるのであれば、pＨ調整のためにどのような緩衝剤および手段を用いてもよい。緩衝剤は、酢酸、クエン酸、リン酸およびホウ酸の緩衝剤を包含する。製剤のpＨを調整するために、必要に応じて酸または塩基を使用し得る。
An osmotic pressure adjusting agent may be added as necessary or expedient. The osmotic pressure adjusting agents include, but are not limited to, salts such as sodium chloride, potassium chloride, mannitol and glycerin, and other suitable osmotic pressure adjusting agents which are ophthalmically acceptable are also used. obtain.
Any buffer and means for adjusting the pH may be used provided that an ophthalmologically acceptable formulation is obtained. Buffering agents include acetic acid, citric acid, phosphoric acid and boric acid buffers. Acids or bases can be used as needed to adjust the pH of the formulation.
同様に、本発明において使用するための眼科学的に許容し得る抗酸化剤は、メタ重亜硫酸ナトリウム、チオ硫酸ナトリウム、アセチルシステイン、ブチル化ヒドロキシアニソールおよびブチル化ヒドロキシトルエンを包含するが、それらに限定されるものではない。
本発明の眼用製剤が含有し得る他の佐剤成分はキレート化剤である。好ましいキレート化剤はエデト酸二ナトリウムであるが、その代わりに、またはそれと組み合わせて他のキレート化剤も使用し得る。
Similarly, ophthalmologically acceptable antioxidants for use in the present invention include sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxytoluene, including It is not limited.
Another adjuvant component that the ophthalmic preparation of the present invention may contain is a chelating agent. A preferred chelating agent is disodium edetate, but other chelating agents may be used instead or in combination.
上記成分は通例、次のような量で使用する：
成分 量(％w／v)
活性成分 約０.００１〜５
保存剤 ０〜０.１０
賦形剤 ０〜４０
浸透圧調整剤 ０〜１０
緩衝剤 ０.０１〜１０
ｐＨ調整剤 q.s.(pH４.５〜８.０)
抗酸化剤 必要量
界面活性剤 必要量
精製水 必要量(１００％とする)
本発明の活性化合物の実際の用量は、化合物によって、および処置する症状によって異なる。当業者はその知識の範囲内で、適当な用量を選択することができる。
本発明の眼用製剤は、眼への適用を容易にするよう、計量適用に適した形態(例えばドロッパー付き容器)に充填することが好都合である。滴下適用に適した容器は通例、不活性で無毒性の適当なプラスチック材料製であり、溶液を約０.５〜１５ml収容する。容器１個が、１単位用量またはそれ以上を含有し得る。
The above ingredients are typically used in the following amounts:
Ingredient amount (% w / v)
Active ingredient about 0.001-5
Preservative 0-0.10
Excipient 0-40
Osmotic pressure regulator 0-10
Buffer 0.01-10
pH adjuster qs (pH 4.5-8.0)
Antioxidant Required amount Surfactant Required amount Purified water Required amount (100%)
The actual dosage of the active compound of the present invention will vary depending on the compound and the condition being treated. One skilled in the art can select an appropriate dose within the knowledge.
The ophthalmic formulation of the present invention is conveniently filled in a form suitable for metering application (eg, a container with a dropper) to facilitate application to the eye. Containers suitable for drop application are typically made of suitable plastic materials that are inert and non-toxic and contain about 0.5 to 15 ml of solution. One container may contain one unit dose or more.
約１０単位用量まで、好ましくは約５単位用量までを含有する再密閉不可能な容器内に入った、特に保存剤不含有の溶液をしばしば調製する。単位用量は通例、１〜約８滴、好ましくは１〜約３滴である。１滴の体積は通例、約２０〜３５μlである。
以下の実施例によって本発明を更に説明するが、実施例は本発明を制限するものではない。
Often, a preservative-free solution is often prepared in a non-resealable container containing up to about 10 unit doses, preferably up to about 5 unit doses. The unit dose is typically 1 to about 8 drops, preferably 1 to about 3 drops. The volume of one drop is typically about 20-35 μl.
The following examples further illustrate the invention, but the examples are not intended to limit the invention.
実施例１
(±)トランス−２−[４−(１−ヒドロキシヘキシル)フェニル]−５−オキソシクロペンタンヘプタン酸およびその低級アルキルエステル
標記酸化合物はよく知られており、購入、または当分野で既知の方法で合成し得る。この化合物の低級アルキルエステルは、発明の背景に挙げた種々の特許出願に記載されたエステル化方法によって合成し得る。
Example 1
(±) trans-2- [4- (1-hydroxyhexyl) phenyl] -5-oxocyclopentaneheptanoic acid and its lower alkyl esters Title acid compounds are well known, purchased, or methods known in the art Can be synthesized. The lower alkyl esters of this compound can be synthesized by the esterification methods described in the various patent applications listed in the background of the invention.
実施例２
眼圧
正常なサルにおいて、気動眼圧測定法により、眼圧を測定した。試験は、気動眼圧測定に馴らした意識のある動物に対して行った。実施例１の化合物を２５μl滴として一方の眼に局所投与した。もう一方の眼には、対照として賦形剤を投与した。スチューデントのペアド(paired)ｔ検定によって、統計学的分析を行った。
眼圧測定結果を第１表に示す。
Example 2
Intraocular pressure In normal monkeys, intraocular pressure was measured by the pneumatic tonometry method. The test was conducted on conscious animals accustomed to pneumatic tonometry. The compound of Example 1 was administered topically to one eye as 25 μl drops. The other eye received vehicle as a control. Statistical analysis was performed by Student's paired t test.
The results of intraocular pressure measurement are shown in Table 1.
実施例３
レーザー処置後の眼圧降下
レーザーによって眼圧を上昇したサルにおいても、眼圧降下を達成した。周囲アルゴンレーザー処置による小柱網の光凝固によって、高眼圧を誘発した。
Example 3
Reduction of intraocular pressure after laser treatment In monkeys whose intraocular pressure was increased by laser, intraocular pressure reduction was also achieved. High intraocular pressure was induced by photocoagulation of the trabecular meshwork with ambient argon laser treatment.
実施例４
ＥＰ2受容体活性の評価
ＥＰ2受容体活性は、ウッドウォードら、プロスタグランジンズ、第３７１−３８３頁、１９９３に記載の方法に従って測定し得る。該文献を引用により本発明の一部とする。
以上の記載は、本発明の実施に用い得る特定の方法および組成物を詳細に説明するものであり、好ましい態様を示すものである。しかし、当業者には、他の薬剤組成物を調製し、使用して、同様の結果を得ることができることが明らかである。すなわち、他のＥＰ2受容体作動剤、例えば１９Ｒ(ＯＨ)ＰＧＥ2[ブタプロスト(butaprost)]なども、動物の眼圧を有効に降下し得、本発明の広い範囲に包含される。
Example 4
Evaluation EP 2 receptor activity EP 2 receptor activity, Woodward et al., Prostaglandins lens, pp 371-383, may be measured according to the method described in 1993. This document is incorporated herein by reference.
The foregoing description details specific methods and compositions that can be employed to practice the present invention, and represents preferred embodiments. However, it will be apparent to those skilled in the art that other pharmaceutical compositions can be prepared and used to achieve similar results. That is, other EP 2 receptor agonists such as 19R (OH) PGE 2 [butaprost] can effectively reduce the intraocular pressure of animals and are encompassed within the broad scope of the present invention.
Claims (11)
Applications Claiming Priority (1)
| Application Number | Priority Date | Filing Date | Title |
|---|---|---|---|
| US08/183,682 US5462968A (en) | 1994-01-19 | 1994-01-19 | EP2 -receptor agonists as agents for lowering intraocular pressure |
Related Parent Applications (1)
| Application Number | Title | Priority Date | Filing Date |
|---|---|---|---|
| JP51958195A Division JP4275194B2 (en) | 1994-01-19 | 1995-01-09 | EP as lowering intraocular pressure ▲ Lower ▼ Receptor agonist |
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| Publication Number | Publication Date |
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| JP2008214351A true JP2008214351A (en) | 2008-09-18 |
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| JP2008080956A Pending JP2008214351A (en) | 1994-01-19 | 2008-03-26 | Ep2 acceptor agonist as ocular pressure reducer |
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| JP51958195A Expired - Lifetime JP4275194B2 (en) | 1994-01-19 | 1995-01-09 | EP as lowering intraocular pressure ▲ Lower ▼ Receptor agonist |
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| EP (1) | EP0789687B1 (en) |
| JP (2) | JP4275194B2 (en) |
| AU (1) | AU685591B2 (en) |
| DE (1) | DE69524446T2 (en) |
| ES (1) | ES2168357T3 (en) |
| WO (1) | WO1995019964A1 (en) |
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- 1995-01-09 AU AU17257/95A patent/AU685591B2/en not_active Expired
- 1995-01-09 DE DE69524446T patent/DE69524446T2/en not_active Expired - Lifetime
- 1995-01-09 WO PCT/US1995/000288 patent/WO1995019964A1/en active IP Right Grant
-
2008
- 2008-03-26 JP JP2008080956A patent/JP2008214351A/en active Pending
Also Published As
| Publication number | Publication date |
|---|---|
| AU685591B2 (en) | 1998-01-22 |
| WO1995019964A1 (en) | 1995-07-27 |
| US5462968A (en) | 1995-10-31 |
| DE69524446T2 (en) | 2002-06-27 |
| EP0789687B1 (en) | 2001-12-05 |
| ES2168357T3 (en) | 2002-06-16 |
| EP0789687A1 (en) | 1997-08-20 |
| AU1725795A (en) | 1995-08-08 |
| JP4275194B2 (en) | 2009-06-10 |
| DE69524446D1 (en) | 2002-01-17 |
| JPH09509652A (en) | 1997-09-30 |
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